Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Eur Heart J. 2022 May 1;43(17):1668-1680. doi: 10.1093/eurheartj/ehac049.
Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.
We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors.
We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.
二尖瓣脱垂（MVP）是一种常见的瓣膜性心脏病，在普通成年人群中的患病率>2%。尽管发病率如此之高，但人们对这种疾病的分子机制仍知之甚少，也没有针对这种疾病的医学治疗方法。我们旨在阐明 MVP 的遗传基础，以便更好地理解这种复杂的疾病。
我们对 6 项全基因组关联研究进行了荟萃分析，这些研究共纳入了 4884 例病例和 434649 例对照。我们在主要分析中发现了 14 个与 MVP 相关的位点，在另外对接受二尖瓣手术的部分样本进行分析时，又发现了另外 2 个与 MVP 相关的位点。对表观遗传、转录和蛋白质组学数据的整合，确定了候选 MVP 基因，包括 LMCD1、SPTBN1、LTBP2、TGFB2、NMB 和 ALPK3。我们创建了 MVP 的多基因风险评分（PRS），并证明其在预测 MVP 风险方面优于年龄、性别和临床危险因素。
我们确定了 14 个与 MVP 相关的遗传位点。多项分析确定了候选基因，包括两个转化生长因子-β信号分子和 spectrin β。我们提出了首个用于 MVP 的 PRS，它最终可能有助于在临床环境中对 MVP 筛查的患者进行风险分层。这些发现推进了我们对这种常见的瓣膜性心脏病的认识，并可能为干预提供新的治疗靶点。
